Researchers Examine Mechanisms That Help Cancer Cells Proliferate

A process that limits the number of times a cell divides works much
differently than had been thought, opening the door to potential new
anticancer therapies, researchers at UT Southwestern Medical Center
report in the Aug. 7 issue of the journal Cell.

Most cells in the human body divide only a certain number of times,
via a countdown mechanism that stops them. When the controlling process
goes wrong, the cells divide indefinitely, contributing to cancer
growth.

The number of times a cell divides is determined by special segments
of DNA called telomeres, which are located at the ends of each
chromosome. Every time a cell divides, the telomeres get shorter. When
they are reduced to a certain length, the cell stops dividing.

In the new study, UT Southwestern researchers used both normal and
cancerous human cells to examine closely how telomeres behave during
cell division.

As a cell prepares to divide into two new cells, its ladder-shaped
DNA "unzips," creating two halves, each resembling a single upright of a
ladder with a set of half-length rungs. Fresh genetic material then
fills in the rungs and a second upright. This process creates two
identical sets of chromosomes that will be allotted between the two
cells.

From earlier studies on model organisms such as yeast, scientists
thought that all telomeres replicated late in the stage of overall DNA
replication, and by the same processes. The new study suggests that
telomeres replicate at various times during this stage, except for a
final step that is not completed until the very end, via a different,
unknown mechanism.

"Interfering with replication of telomeres might provide a way to
halt uncontrolled spread of cancer cells," said Dr. Woodring Wright,
professor of cell biology at UT Southwestern and co-senior author of the
paper.

The researchers also examined an enzyme called telomerase, which
"rebuilds" telomeres so they do not get shorter and signals the cell to
stop dividing. Normally, telomerase is only active in cells such as stem
cells and dividing immune cells, which must reproduce constantly.

But telomerase also has a dark side: When active in cancer cells, it
enables unlimited growth, a hallmark of cancer.

It had been thought that telomerase only works on the shortest
telomeres in a cell, but in the new study, the UT Southwestern
researchers found that telomerase rebuilds most or all of the telomeres
in a cell for each division, not just the shortest ones, as had been
thought.

"Understanding ways to inhibit this telomerase mechanism might lead
to novel anticancer therapies," said Dr. Jerry Shay, professor of cell
biology and co-senior author of the paper.

Clinical trials using a drug that blocks telomerase are already under
way at UT Southwestern for lung cancer and chronic lymphocytic
leukemia.

The new study was possible because the researchers developed a way to
examine the very ends of telomeres after a single cell division.
Previous research in the field required multiple cell divisions to
detect such changes.

"Now that we can look at what telomerase is doing in a single
cell-division cycle, there is potential for a tremendous number of
follow-up studies," Dr. Wright said.